Samenvatting

Mucopolysaccharidosis type I (MPS-I), or Hurler syndrome, is a lysosomal storage disease due to mutations in the gene encoding -L-iduronidase (IDUA), resulting in deficiency of -L-iduronidase and accumulation of glycosaminoglycans (GAGs). Patients suffer from a range of clinical features like skeletal abnormalities, hepatosplenomegaly, severe mental retardation, dysostosis multiplex, corneal clouding, and when untreated, die before the age of 12 due, possibly to cardiac involvement.
To introduce -L-iduronidase into the body, enzyme replacement therapy as well as blood -, bone marrow - and umbilical cord blood transplants are being explored. Cord blood -, bone marrow -, peripheral blood transplantations and enzyme replacement are therapies considered only moderately successful for affected patients, making the development of novel treatment necessary.
Stem cell transplantation (SCT) has been shown to be effective for several important clinical outcome parameters, with mental retardation as the most important one, the reported clinical outcome after successful SCT is variable among Hurler syndrome patients and there are still some limitations, like finding a matching donor. Enzyme replacement therapy (ERT) is a medical treatment replacing an enzyme in patients who lack this particular enzyme, getting the enzyme over the blood-brain barrier or into bones is the biggest problem with this therapy.
Mesenchymal stromal cells (MSCs) are multipotent cells found in the bone marrow that can differentiate into different cell types like, adipocytes, chondrocytes and oseoblasts. The hypothesis is that some of the clinical features that come with the disease may be corrected by the infusion of (allogenic), multipotential, bone marrow-derived mesenchymal stromal cells.
To determine where the MSCs will home to after injection, we have labeled the MSCs and tested a variety of injection routes and compared them with each other. We also tested if age- and pre-treatment of the recipient had an effect on the overall homing of transplanted MSCs.
The intracardial injection route seems to be the most effective route to get the cells into the bones (0,2%) in comparison with an intravenous injection (0,05%). But due to the high mortality rate of a intracardial injection, more study is needed to determine the optimal conditions for this injection. Using younger recipients also increases the homing to the bones with 0,1% of transplanted MSCs found back in 3 weeks old mice and 1% of transplanted MSCs found back in neonatal mice. Pre-treatment of the mice did not have a significant effect on the overall homing of MSCs. These short-term studies suggests that the MSCs can not pass over the blood-brain barrier and deliver the enzyme to the central nervous system but there is still study needed on the long-term homing capacity of MSCs using a lentiviral construct and bioluminescence imager.